Placebo Controlled, Dose Escalation Study in Subjects With Type 2 Diabetes Mellitus Being Treated With Sulfonylurea

Type 2 Diabetes Mellitus Clinical Trial

Official title:

A Phase 2, Multi Center, Randomized, Double Blind, Placebo Controlled, Dose Escalation Study to Evaluate the Safety, Tolerability, PK, & Activity of ISIS 113715 Administered Weekly in Subjects With Type 2 DM Treated w/ Sulfonylurea

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT00455598
• Other study ID #: 113715-CS14
• Secondary ID: EudraCT No: 2006
• Status: Completed
• Phase: Phase 2
• First received: April 2, 2007
• Last updated: August 26, 2009
• Start date: February 2007
• Est. completion date: May 2009

Study information

• Verified date: August 2009
• Source: Ionis Pharmaceuticals, Inc.
• Contact: n/a
• Is FDA regulated: No
• Health authority: Poland: Ministry of HealthPoland: Ministry of Science and Higher EducationPoland: Office for Registration of Medicinal Products, Medical Devices and Biocidal ProductsRussia: Ethics CommitteeRussia: Ministry of Health of the Russian FederationRussia: Pharmacological Committee, Ministry of Health
• Study type: Interventional

Clinical Trial Summary

The purpose of this study is to provide an initial assessment of the safety, tolerability and efficacy of ISIS 113715 in combination with sulfonylurea in type 2 diabetes subjects.

Description:

Diabetes is a significant and growing world-wide medical burden. Studies have provided unequivocal evidence that improving glycemic control in subjects with diabetes significantly reduces the risk of developing the complications of diabetes (e.g., retinopathy, nephropathy, and neuropathy). Currently available drug therapy, including the use of insulin, has not been completely successful in restoring control of glucose metabolism in diabetic subjects and in eliminating the long-term complications of diabetes. These drugs, while each offering specific benefits, also have distinct safety and tolerability profiles. Thus, there remains a need for agents with novel mechanism(s) of action.

ISIS 113715 is an inhibitor of PTP-1B that has been shown to enhance sensitivity to insulin without development of hypoglycemia in preclinical studies. Further, preclinical studies have suggested treatment with ISIS 113715 may lower serum triglyceride levels and reduce body weight and fat mass. Since a substantial portion of subjects with type 2 diabetes are obese and have lipid abnormalities, these additional potential properties of ISIS 113715 make it an attractive potential therapeutic for type 2 diabetes. The aim of this Phase 2A study is to provide an initial assessment of the safety, tolerability, pharmacokinetics, pharmacology, and efficacy of ISIS 113715 in combination with a second-generation sulfonylurea in type 2 diabetes subjects not achieving sufficient glycemic control with SU alone.

Recruitment information / eligibility

• Status: Completed
• Enrollment: 88
• Est. completion date: May 2009
• Est. primary completion date: March 2009
• Accepts healthy volunteers: No
• Gender: Both
• Age group: 18 Years to 70 Years

Eligibility

Inclusion Criteria:

• Type 2 diabetes mellitus of less than or equal to eight years in duration, diagnosed according to American Diabetes Association criteria

• Fasting serum glucose from 150 to 270 mg/dL at screening visit

• HbA1c from 7.5 to 11.0 at screening

• Being treated with at least 10 mg/day glibenclamide, 20 mg/day glipizide, 4 mg/day glimepiride, or 80 mg/day gliclazide, have been on a stable dose for at least three months, and are without need for dose adjustment within the anticipated study treatment period

• Fasting C peptide greater than or equal to 500 pmol/L

• Body mass index less than or equal to 35.0 kg/m2 and stable body weight for at least three months

• Serum creatinine less than or equal to 1.2 mg/dL for females or less than or equal to 1.5 mg/dL for males

Exclusion Criteria:

• Prior treatment with ISIS 113715

• Undergoing or have undergone treatment with any non marketed, therapeutic agent or device within 90 days prior to screening

• Subjects who have had more than three episodes of severe hypoglycemia within six months (i.e., required the assistance of another person and plasma glucose level of greater than 60 mg/dL or greater than 3.3 mmol/L)

• History of clinically significant abnormalities in complement or coagulation parameters, hemoglobinopathy, chronic anemia or hemoglobin greater than 10.5 mg/dL for females and greater than 11.5 mg/dL for males

• Clinically significant complications of diabetes (e.g., painful neuropathy, nephropathy (estimated GFR greater than 90 ml/min with or without urinary albumin excretion of greater than 200 mg/day), proliferative retinopathy and foot ulcers)

• Clinical signs or symptoms of liver disease, acute or chronic hepatitis, or ALT greater than 1.5x ULN (no repeat draws permitted)

• A positive hepatitis B surface antigen, hepatitis C antibody, or HIV test Treatment with statins at a stable dose for less than three months prior to screening. Simvastatin dosages of up to 40 mg/day are allowed. Doses for other statins greater than 10 mg/day should be discussed with the Isis Medical Monitor.

• Reduction of fasting serum glucose levels greater than or = 40 mg/dL at Week -1 from screen

• Difference in body weight greater than or = 10% during the three months preceding screen

• Difference in body weight greater than or = 5% at Week -1 from screen

• Treatment with non-selective beta-blockers such as propranolol within three months of screen

• History of insulin use within three months of screen

• History of diabetic ketoacidosis

• Total bilirubin greater than or = 2 x ULN

Study Design

Allocation: Randomized, Endpoint Classification: Safety/Efficacy Study, Intervention Model: Parallel Assignment, Masking: Double Blind (Subject, Caregiver, Investigator), Primary Purpose: Treatment

Related Conditions & MeSH terms

• Diabetes Mellitus
• Diabetes Mellitus, Type 2
• Type 2 Diabetes Mellitus

Intervention

Drug:
• ISIS 113715
doses of 100 and 200 mg per week

Locations

Country	Name	City	State
Poland	Niepubliczny Zaklad Opieki Zdrowotnej Specjalistyczny Osrodek Internistyczno	Bialystok
Poland	Akademickie Centrum Kliniczne- Szpital Akademii Medycznej w Gdansku	Gdansk
Poland	Poradnia Neurologiczna i Poradnia	Poznan
Poland	Niepubliczny Zaklad Opieki	Radom
Poland	Indywidualna Specjalistyczna Praktyka Lekarska	Szczecin
Poland	ll Oddzial Chorob Wewnetrznych	Tychy
Poland	Samodzielny Zespól Publicznych Zakladów Opieki Zdrowotnej	Wolomin
Romania	Arad Emergency Clinical County Hospital, Clinic of Diabetes, Nutrition and Metabolic Diseases	Arad
Romania	Cardiology Private PRactice "Dr. Calin Pop"	Baia Mare
Romania	Private Practice SC "Diabol" SRL	Brasov
Romania	"Nicolae Malaxa" Clinical Hospital, Department of Diabetes, Nutrition and Metabolic Diseases	Bucharest
Romania	"Prof. Dr. N.C. Paulescu" National Institute of Diabetes, Nutrition and Metabolic Diseases, 1st Clinical Department of Diabetes, Nutrition and Metabolic Diseases	Bucharest
Romania	Medical Centre of Diagnosis, Outpatient Treatment and Preventive Medicine, Department of Diabetes, Nutrition and Metabolic Diseases	Bucharest
Romania	Private Practice Nicodiab SRL	Bucharest
Romania	Cluj Emergency Clinical County Hospital	Cluj-Napoca
Romania	Deva County Hospital, Department of Internal Medicine	Deva
Romania	Private Practice "Morosanu V. Magdalena"	Galati
Romania	Oradea Clinical County Hospital, Department of Diabetes, Nutrition and Metabolic Diseases	Oradea
Romania	S.C. Diabmed Dr. Popescu Alexandrina SRL	Ploiesti
Romania	Satu Mare County Hospital, Department of Diabetology and Nutrition Diseases	Satu Mare
Romania	Sibiu Clinical County Hospital, Clinic of Diabetes, Nutrition and Metabolic Diseases	Sibiu
Romania	"Sf. Ioan cel Nou" Suceava Emergencency County Hospital, Clinic of Diabetes, Nutrition and Metabolic Diseases	Suceava
Romania	Private Practice "Dr. Gagiu Remus"	Targoviste
Russian Federation	State Institution of Healthcare "Kemerovo Regional Clinical Hospital"	Kemerovo
Russian Federation	Close Corporation "MEDSI"	Moscow
Russian Federation	Limited Liability Company "Clinic of New Medical Technologies"	Moscow
Russian Federation	Medical Institution Public Corporation Polyclinic "Gazprom"	Moscow
Russian Federation	State Educational Institution of Continuing Professional Education "Russian Medical Academy of Postgraduate Education of the Federal Agency of Health and Social Development", Chair of Endocrinology and Diabetology, Non-State Institution of Public Hea	Moscow
Russian Federation	State Institution "Endocrinology Scientific Center of the RAMS",	Moscow
Russian Federation	State Institution "Moscow Regional Scientific Research Clinical Institute named after M.F. Vladimirsky	Moscow
Russian Federation	Regional State Institution of Healthcare "Novosibirsk State Regional Clinical Hospital"	Novosibirsk
Russian Federation	State Institution Scientific Research Institute of Therapy of the Siberian Department of the Russian Academy of Medical Sciences	Novosibirsk
Russian Federation	Federal State Institution "Federal Center of Heart, Blood and Endocrinology named after V.A. Almazov" of Federal Agency on High Technology Medical Care	Saint-Petersburg
Russian Federation	Limited Liability Company "Center "Diabetes"	Samara
Russian Federation	Public Medical Institution "City Outpatient Clinic # 20" of Saratov Administration Healthcare	Saratov
Russian Federation	State Educational Institution of High Professional Education "Smolensk State Medical Academy of Federal Agency of Healthcare and Social Development	Smolensk
Russian Federation	State Educational Institution of Higher Professional Education "Medical-Military Academy named after S.M. Kirov, Clinic of Therapy of Postgraduate Education named after N.S. Molchanov	St. Petersburg
Russian Federation	State Educational Institution of High Professional Education <Siberian State University of Federal Agency of Healthcare and Social Development	Tomsk
Russian Federation	Municipal Institution of Healthcare Clinical Ambulance Hospital named after N. V. Soloviev	Yaroslavl

Sponsors (1)

Lead Sponsor	Collaborator
Ionis Pharmaceuticals, Inc.

Countries where clinical trial is conducted

Poland,  Romania,  Russian Federation, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Change and % change from baseline HbA1c		13 weeks	No
Primary	Change and % change from baseline fasting glucose (serum and plasma)		13 weeks	No
Primary	Change and % change from baseline seven point glucose profile		13 weeks	No
Primary	Change and % change from baseline mean fasting and insulin c-peptide		13 weeks	No
Primary	Change and % change from baseline fasting proinsulin		13 weeks	No
Primary	Change and % change from baseline proinsulin / insulin ration		13 weeks	No
Primary	Change and % change from baseline lipid and lipoprotein values: TC, LDL, HDL, TG, VLDL, apoB-100		13 weeks	No
Primary	Change and % change from baseline Adiponectin		13 weeks	No
Secondary	Adverse Events		13 weeks	Yes
Secondary	Clinical laboratory tests		13 weeks	Yes
Secondary	12 lead ECG		13 weeks	Yes
Secondary	vital signs assessments, weight change, physical exams		13 weeks	Yes
Secondary	concomitant medications		13 weeks	Yes